PROJECT 1 SUMMARY There is growing emphasis on elucidating neurobiological and cognitive changes associated with Alzheimer s disease (AD) at the earliest point possible. In the absence of AD, however, cognition is also impacted by aging and subtle distinctions between normal and pathological processes are difficult to detect. The proposed project focuses on the complexity of the hippocampal circuit, regionally distributed white matter abnormalities, and refined neuropsychological instrumentation to understand differences between pathological aging and normal aging, defined as having cerebrospinal fluid evidence of AD or not. Recent studies suggest that two regions of the hippocampal circuit that seem to be most relevant in AD and aging are the entorhinal cortex, particularly its lateral extent, and the dentate gyrus. Postmortem, neuroimaging, and behavioral studies show that the dentate gyrus is differentially affected by aging and that pattern separation is the cognitive operation closely linked to normal aging and dentate gyrus function. In contrast, entorhinal cortex appears to be the region affected first in AD and retention of information over a brief interval is a cognitive metric strongly associated with entorhinal cortex function and commonly impacted early in AD. A parallel line of research implicates regionally-distributed white matter abnormalities, visualized as white matter hyperintensities on magnetic resonance imaging, in AD and severity of cognitive symptoms in aging. Whereas frontal lobe white matter hyperintensity volume is elevated among older adults with any cognitive impairment, parietal lobe white matter hyperintensities specifically appear to be implicated in AD. Human studies examining hippocampal subregion and regional white matter hyperintensities in AD and aging have been limited because they generally have not incorporated AD biological marker information. The goal of the proposed study is to use recently developed in vivo tools to determine whether the specific loci within the hippocampal circuitry and the regional distribution of white matter hyperintensities are linked to AD and aging. Participants (n=150) will receive a lumbar puncture and be classified as having cerebrospinal fluid evidence suggestive of AD. High resolution functional and structural magnetic resonance imaging will be used to quantify regional hippocampal function and regional white matter hyperintensities volume. Participants will be evaluated with a neuropsychological battery comprising tests that, studies suggest, appear sensitive to AD/entorhinal cortex and normal aging/dentate gyrus function. We will compare individuals with and without cerebrospinal evidence of AD, examine the relationship of AD biological markers with hippocampal function and white matter hyperintensities, test the degree to which hippocampal dysfunction and white matter abnormalities interact, and conduct preliminary longitudinal analysis to test the degree to which regional hippocampal dysfunction and regional WMH predict decline in performance on tests designed to evaluate changes due to aging and AD.